|Year : 2016 | Volume
| Issue : 1 | Page : 1-4
Steroid-sparing medications in thyroid eye disease
Ali Ahmadzadeh-Amiri1, Ahmad Ahmadzadeh-Amiri2
1 Medical Student Research Committee, Tehran University of Medical Sciences, Tehran, Iran
2 Department of Eye, Medical Faculty of Medicine, Bu Ali-Sina Hospital, Mazandaran University of Medical Sciences, Mazandaran, Iran
|Date of Web Publication||17-Jun-2016|
Department of Eye, Medical Faculty of Medicine, Bu Ali-Sina Hospital, Mazandaran University of Medical Sciences, Mazandaran
Source of Support: None, Conflict of Interest: None
Thyroid eye disease (TED) is a heterogeneous autoimmune reaction typically occurring in the orbit of middle age group. The orbital inflammation of Graves' disease may parallel or remain isolated from a related inflammatory reaction in the thyroid gland. Development and severity of TED may dependent to both endogenous (genetic factors, increased age, male sex) and, or exogenous factors (smoking, thyroid dysfunction, and radioiodine treatment). Although rescue medical therapy for severe TED is often initiated with glucocorticoids, steroid-sparing medications may be an alternative area of efficient treatment.
Keywords: Graves' disease, steroid-sparing medications, thyroid eye disease
|How to cite this article:|
Ahmadzadeh-Amiri A, Ahmadzadeh-Amiri A. Steroid-sparing medications in thyroid eye disease. Sudanese J Ophthalmol 2016;8:1-4
| Introduction|| |
Lymphocytic orbital inflammation that caused by autoimmune process may lead to thyroid eye disease (TED). Although it occasionally be associated with hypothyroid or euthyroid states, it commonly noted in Graves's hyperthyroidism. The Graves's disease is more prevalent in women, with 1.9% in females and about 0.19% in males and annual incidence of 16 and 2.9 cases per 100,000 in women and men, respectively, however, severe cases occur more often in men than in women. Sera of patients with Graves's disease have a powerful thyroid-stimulating factor that had a longer duration of action than that of thyrotropin, the long-acting thyroid stimulator.,,, Antigenic cross-reactivity of orbital and thyroid tissue, lead to stimulation of proteins of the extraocular muscles and orbital fat by circulating thyroid antibodies, resulting in fibroproliferation and glycosaminoglycans production. Orbital congestion and exophthalmos, ocular dysmotility, diplopia, and rarely compressive optic neuropathy are consequent. Active phase of Graves's disease, typically occurred in 6-24 months, followed by progression to plateau inactive disease. This course is often stable with rarely reactivation.
Achieving to euthyroid state is an important goal of TED treatment. Tobacco smoking is a strongest modifiable risk factors for disease progression which carries at least 7.7 time for developing TED compared to not smoking, as well as severity of active disease with up-regulates inflammatory cytokines.,,, The mainstay of treatment for sever active TED with visual threaten or corneal exposure, is corticosteroid therapy and/or orbital decompression surgery. Investigation in the efficacy of nutritional supplements, steroid-sparing agents, orbital radiation therapy, and various surgical interventions are the new era of TED management. Rituximab as a steroid-sparing medication is a most important in this category.
The present review provides an update on steroid-sparing treatment of TED till March 2015. The literature was searched from the sources such as electronic database of PubMed, English from inception to March 2015.
| Steroid-Sparing Regimens|| |
The first-line treatment of moderate to severe active TED continues to be corticosteroids. The American Society of Ophthalmic Plastic and Reconstructive Surgery showed that using and preferring oral corticosteroids over intravenous (IV) in the first choice treatment of severe TED. Although corticosteroid, being well known effective treatment, harbors a significant adverse effects such as hypertension, hyperglycemia, acute liver disease, weight gain, mood instability, as well as osteoporosis. As such, steroid-sparing regimens have new modality evolve with a wide target to, thyroid-stimulating hormone receptor, insulin-like growth factor-1 receptor (IGF-1R), B-cells, T-cells, and other inflammatory cytokines.
Marcocci et al. were shown some antioxidant supplementation such as selenium may help patients with mild Graves' orbitopathy and selenium deficiency.
According to Yoon et al. study, quercetin, a natural plant extract that found in food such as capers, may inhibitory effect on proinflammatory cytokines and has been recommended for Graves' orbitopathy.
Recent research focuses on biologic factors including rituximab, adalimumab, and teprotumumab.
Rituximab is an engineered chimeric mouse-human monoclonal IgG1 kappa antibody directed against the CD20 antigen. It produced by mammalian cell suspension culture in a nutrient medium containing the antibiotic gentamicin that cleared in the final product. It recognized as B-cell lymphocytes inhibitor for treatment of rheumatoid arthritis and lymphoma, approved by FDA that may also have a role in the treatment of TED. Clinical randomized study comparing rituximab and methylprednisolone pulse therapy in moderate-to-severe TED revealed that 32 patients received either treatment with the primary endpoint of a decrease in the clinical activity score (CAS), and with secondary endpoints of improvements in proptosis, extraocular motility, diplopia, and quality of life as assessed by a questionnaire. At 24 weeks, all patients satisfied the primary endpoint, but 100% of patients had clinical improvement compared to only 68.7% of patients treated with steroid. Furthermore, disease reactivation occurred in five patients treated with IV steroid, whereas none reactivated with rituximab. Recent review of eight patients with severe orbitopathy shown that rituximab was efficient. These patients with two infusions of rituximab 2 weeks apart had CAS score improvement and reduction in the proportion of IGF-1R CD3+ T-cells.
The pivotal role of rituximab in the TED management, however, remains unclear. Gess and Silkissreport a case of rituximab treatment failure with B-cell depletion from the blood and orbital fat of a TED patient who require orbital decompression for disease progression. Another, randomized, placebo-controlled trial in 21 patients with TED, compared treatment with two rituximab infusions versus two saline infusions, given 2 weeks apart, found that at 24 and 52 weeks, there was no significant difference in the improvement of the primary endpoint of CAS score or in their secondary endpoints, including lagophthalmos, exophthalmos, or diplopia in the rituximab group, fail to prove any benefit of this treatment. As such, the data about rituximab remain contradictory in the management of TED.
Adalimumab is a fully human monoclonal antibody and tumor necrosis factor (TNF)-α inhibitor approved for the treatment of rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, inflammatory bowel disease, chronic plaque psoriasis, and polyarticular juvenile idiopathic arthritis; it has also been used for reducing inflammation in the treatment of active TED. Retrospective review of Ayabe et al. in ten patients with inflammatory-stage TED demonstrated that six patients had a decrease in their orbitopathy, eight patients were found to taper steroids while on adalimumab, and significant improvement in the CAS score in 5 individuals with the most active disease.
Teprotumumab is a human monoclonal anti-IGF-1R blocking antibody, which designed for the treatment of solid and hematologic tumors and is currently also undergoing phase 2 clinical trials in patients with inflammatory-stage TED. A recent study showed that fibrocytes from patients with active TED had highly expressed TSH receptor and IGF-1R. As teprotumumab-treated fibrocytes display attenuated expression of IGF-1R and TSH receptor, implies that teprotumumab could have a rationale role in future research for therapeutic efficacy in preventing TED.
Tocilizumab is a humanized antihuman interleukin (IL)-6 receptor antibody which is used to treat rheumatoid arthritis. Pérez-Moreiras et al. found in prospective study that 4 of 18 steroid-resistant patients with active TED were well-treated with weekly IV tocilizumab for four cycles. They also noted that 15 patients showing improvement of extraocular motility and 13 patients showing proptosis recovery.
Studies on anti-inflammatory agents to cytokines inhibition that influence the pathogenesis of TED focuses on studies of IL-6, IL-8, TNF, and interferon-γ (IFN-γ). Tanshinone, a molecule isolated from the Chinese plant salvia miltiorrhiza, carried anti-inflammatory and antioxidative properties. Tanshinone IIA is available in the form of purified sulfonate salts can reduce expression of IL-6 and IL-8 in orbital fibroblasts, amount of reactive oxygen species, and degree of adipogenesis on orbital tissue obtained from orbital decompression surgeries from patients with TED.
Active TED associated with elevation of IFN-γ, a potent cytokine that can induce the secretion of proteins such as the alpha chemokine IFN-γ-induced protein (IP-10). Levels of IP-10 are reduced after treatment with steroids and radiation in inflammatory TED cause IP-10 level reduction. Lee et al. study revealed that benzylidene acetophenone derivatives can decrease IPs, such as IP-10, in orbital fibroblasts of TED.
Octreotide, a synthetic somatostatin analog, is thought a beneficial effect on some cases of TED. Lanreotide is a longer-acting somatostatin analog, has a good response. Pentoxifylline and nicotinamide thought to inhibit cytokine-induced glycosaminoglycan synthesis in retro-orbital fibroblasts may also be useful. Plasmapheresis and IV immunoglobulin in treatment of active TED is not well specified. Kahaly et al. explored randomized trial of IV immunoglobulin versus oral prednisolone, both treatments had equal effect in management of active TED.
| Conclusion|| |
TED is a devastating condition that troubles for both patients and its providers. Abundance of present report in this review illustrates efforts for treatment of TED continues by clinicians and scientists. However, the majority had limited due to weaknesses in several item including Relatively low case numbers, absence of proper controls, disparate method, and distinct grading designs. Spontaneous recovery of inflammation over time as a natural history of TED is another confounding factor that is difficult to control in studies. Nevertheless, there have been some actual improvements with expansion of steroid-sparing agents in a number of patients who have failed corticosteroid treatment.
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Conflicts of interest
There are no conflicts of interest.
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